Cancer of the liver is a rare malignancy in the United States, but in parts of Asia and Africa, it is one of the most common malignancies. The areas of highest incidence are in eastern Asia and sub-Saharan Africa, and HCC can be the dominant cause of cancer mortality in these areas. Although incidence is very low in Western countries, ethnic subgroups in these populations may be at very high risk due to the high prevalence of chronic hepatitis B virus (HBV) infection. Because survival times for patients with HCC are short, incidence and mortality figures are roughly equivalent. In the United States, 5-year survival rates for liver cancers over the past two decades remain at about 5%.
The epidemiologic association of chronic HBV or HCV infection with hepatocellular carcinoma has been well established. For patients with chronic viral hepatitis, screening for early-stage hepatocellular carcinoma may permit the institution of curative treatment strategies, and antiviral treatment may reduce the risk of subsequent development of hepatocellular carcinoma. For patients with established hepatocellular carcinoma, the presence of concurrent chronic viral hepatitis or cirrhosis may affect prognosis and survival and may alter treatment options because of impaired hepatic function.
Incidence of hepatocellular carcinoma increases with age, with the age of peak incidence varying somewhat with population. HCC is seen in childhood in areas where HBV is endemic and infection occurs primarily at birth or early childhood. In all populations worldwide, there is a strong male predominance in HCC incidence. Several possible explanations for this have been proposed, including higher rates of HBV carriage among males, genetic susceptibility, androgenic steroids, higher body iron stores, and higher exposure to other hepatocarcinogenic cofactors (e.g., alcohol, aflatoxin).
Familial aggregation of HCC has been reported, primarily in families where chronic HBV infection is also present. Some studies, however, have found an effect of family history independent of HBV status. Familial aggregation may be explained by the interaction of HBV and a major gene. Familial aggregation has also been reported for hepatoblastoma, which occurs in families carrying germline mutations of the APC (adenomatous polyposis coli) gene.
Because of the high prevalence of HBV infection in certain regions of China, a screening program for hepatocellular carcinoma was instituted for adults over the age of 35 with chronic HBV infection. The screening tests used were serum alpha-fetoprotein (AFP) and liver ultrasonography performed every 6 months. The AFP has a sensitivity of 70%, since up to 30% of hepatocellular carcinomas do not secrete it. Liver ultrasonography has up to 70% sensitivity for the detection of HCCs that are less than 2 cm, but has poor specificity. The combination of AFP and ultrasonography, however, increases both sensitivity and specificity.
The prognosis for liver carcinoma patients is poor. Patients with metastatic or locally advanced HCC usually respond poorly to anticancer treatments. Untreated patients usually die in 3-4 months; treated patients may live 6 to 18 months if they respond to therapy. Long-term survival is seen occasionally after successful subtotal hepatectomy for noninvasive carcinoma. Because the normal metabolic and storage functions of the liver are impaired, patients are at risk for nutritional and bleeding complications. Patients with advanced cirrhosis commonly succumb to complications such as encephalopathy, variceal hemorrhage, and sepsis, independently of the tumor's extent.
Treatment decisions are also based on the presence of active hepatitis or cirrhosis. Doxorubicin, the most active chemotherapy agent for HCC, is metabolized and excreted by the liver. The pharmacokinetics for doxorubicin may be changed for patients with liver dysfunction, resulting in enhanced toxicity. Hepatic resection, a treatment of choice for solitary HCC, can result in hepatic failure if hepatic reserve is compromised by hepatitis or cirrhosis. For patients with unresectable HCC, orthotopic liver transplantations have produced prolonged survival. Patients with stage I or II HCC have 5-year survivals following transplantation that are comparable to those of patients transplanted for cirrhosis without HCC. This survival advantage is attenuated, however, in patients with active HBV viral replication (HBeAg or high levels of HBV DNA) because of the high incidence of severe viral re-infections of the liver allograft. Although patients with HCV infection also have a high incidence of re-infection following transplantation, the disease is indolent and eventual cirrhosis may not occur for decades.
Several viruses have recently come forth as both vehicles for gene therapy and as candidate anticancer agents. Among them adenovirus, a mildly pathogenic human virus that propagates prolifically in epithelial cells, the origin of many human cancers. Adenovirus has emerged as a virus that can be engineered with oncotropic properties. See, for example, U.S. Pat. No. 5,846,945 (Onyx); U.S. Pat. No. 5,801,029 (Onyx); U.S. Pat. No. 5,747,469 (Univ Texas); PCTUS1999/08592 (WO 99/59604; Onyx) or PCT/US1998/03514 (WO 98/35554; Canji); PCT/US1997/22036 (WO 98/29555; Onyx). Replication competent adenovirus vectors have been designed to selectively replicate in tumor cells. Improving the delivery of these adenoviruses, both to local-regional and disseminated disease, as well as improving the virus to promote intratumoral spread are of particular interest.
Several experimental cancer therapies utilize various aspects of adenovirus or adenovirus vectors. See, for example, U.S. Pat. Nos. 5,846,945; 5,801,029; PCT/US99/08592; U.S. Pat. No. 5,747,469; PCT/US98/03514; and PCT/US97/22036.
Although replication competent adenoviruses may be able to achieve selective targeting and amplification for the treatment of local and disseminated cancer, there remains a need for improvement in both the adenovirus vectors themselves and methods for their use. Preliminary results suggest that the features of effective treatment strategies for various types of cancer may require development of specific adenovirus vectors and/or methods particular to the type of cancer under treatment. Although chemotherapy and immunotherapy are the most prevalent current therapeutic strategies for disseminated tumors, both toxic side effects and lack of efficacy remain a problem.
There is, therefore, substantial interest in development of viral vectors which enable the targeting of specific cancers in vivo.